Major depression has been estimated to affect 10 percent of the population, it is associated with significant morbidity and mortality, and the current expenditure on antidepressant medications is estimated to exceed $3 billion annually. Disturbances in central serotonin (5-HT) functioning appear to have an important role in the psychobiology of depression and its treatment. Prior investigation of 5-HT systems in depression have been limited by a lack of techniques that can directly examine the relevant neuronal structures in humans. The objective of this proposal is to characterize the specific neurotransmitter/receptor dysfunction in 5-HT pathways in depressed patients and the timecourse of antidepressant-induced changes. The investigator proposes to use PET imaging of serotonin (5-HT) receptors to characterize the changes in 5-HT function across different brain regions in depressed patients. Using a longitudinal design, he will obtain in vivo quantitation of cortical and subcortical 5-HT2 receptors at three points during antidepressant treatment; prior to beginning treatment, after two days of treatment and after eight or sixteen weeks of treatment. This sequence will allow direct examination of 5-HT receptors in the unmedicated depressed state, changes in receptors due to acute antidepressant treatment, and changes in receptors following chronic treatment. He proposes to study three groups of patients in order to distinguish the role of the pharmacological properties of different antidepressant treatments from state-related changes associated with recovery. One group will be treated with paroxetine, a selective serotonin reuptake inhibitor; a second group will be treated with DMI, a tricyclic with a relatively potent and selective inhibition of norepinephrine reuptake; and a third group will receive a nonpharmacological treatment, interpersonal psychotherapy. Additionally, he will obtain comparable assessments of 5-HT function in a group of untreated normal controls to establish the physiological variability of these receptor measures and compare for baseline differences in the depressed patients. The information gathered in this project is expected to make a significant contribution to out understanding of the neurobiology of depressive disorders and its treatments. A clearer understanding of the changes in the neurotransmitter systems during pharmacological and other treatments of depression should provide an improved rationale for the development of efficacious interventions in the future.